New Orally Active Non-Peptide Fibrinogen Receptor (GpIIb-IIIa) Antagonists: Identification of Ethyl 3-[N-[4-[4-[Amino[(ethoxycarbonyl)imino]methyl]phenyl]- 1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl]piperid-4-yl]amino]propionate (SR 121787) as a Potent and Long-Acting Antithrombotic Agent

Abstract

The platelet fibrinogen receptor GpIIb-IIIa is curently considered a target of choice for drugs used in the prevention and treatment of thrombosis. Ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl)imino]methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl]piperid-4-yl]amino]propionate (6, SR 121787) is a new antiaggregating agent which generates in vivo the corresponding diacid 19d (SR 121566), a non-peptide GpIIb-IIIa antagonist. In vitro, 19d inhibited ADP-induced aggregation of human and baboon platelets (IC₅₀ = 46 ± 11 and 54 ± 6 nM, respectively), and on human platelets, 19d antagonized the binding of ¹²⁵I-labeled fibrinogen (IC₅₀ = 19.2 ± 6.2 nM). Ex vivo, 8 h after an iv administration of 19d (100 μg/kg, iv) to baboons, ADP-induced aggregation was strongly inhibited (more than 90%). At 8 h, the ED₅₀ value was 24 ± 3.3 μg/kg), and even 24 h after the administration of a single dose of 100 μg/kg of 19d, platelet aggregation was still significantly inhibited (50 ± 6% inhibition, P < 0.05). In the same species, the oral administration of 500 μg/kg of 6 produced a nearly complete inhibition of aggregation for up to 8 h (ED₅₀ at 8 h was 193 ± 20 μg/kg). After an oral dose of 2 mg/kg of 6, an antiaggregating effect was still observed at 24 h (44 ± 12% inhibition, P < 0.05). 6 was well tolerated in animals, showing that, on the basis of these studies, it is a suitable candidate for development as an orally active antithrombotic agent.